Recombinant human liver phenylalanine hydroxylase is severely inhibited by 7-substituted pterin (7-BH4) in the presence of the natural cofactor tetrahydrobiopterin. Our results suggest that the 7-substituted pterin might be responsible for causing mild hyperphenylalaninemia in patients who excrete 7-BH4 in their urine. We have succeeded in crystallizing a mutant form of the phenylalanine hydroxylase for x-ray analysis.